Comparing students' performance in self-directed and directed self-learning in College of Medicine, University of Bisha.

Background: Student-centered learning strategy increases the likelihood of graduation of competent, self-dependent, and problem-solving physicians. The University of Bisha, College of Medicine (UBCOM) adopted self-directed learning (SDL) represented by problem-based learning (PBL), and directed self-learning (DSL) represented by team-based learning (TBL). Aim: To compare the students' performance in SDL and DSL among UBCOM students. Methodology: A total of 502 multiple choice questions (MCQs) from the mid-course and final exams were collected by the relevant subject experts from nine courses during the period from September 2020 till June 2023 that adopted PBL and TBL; 247 MCQs related to PBL and 255 related to TBL. Psychometric analysis was used to determine difficult, easy, and optimum questions (≤25%, ≥90%, and 26-89%, respectively). Point biserial as <0.19, 0.20-0.29, 0.30-0.39, and >0.40 which indicate poor, marginal, good, and excellent point biserial, respectively. Finally, the number of functional distractors was attempted by >5% of the candidates. Results: No significant differences were noted for the students' performance in MCQs related to PBL (representing self-directed, small group learning tool), and TBL (representing directed-self, large group learning tool) regarding difficulty index (DI), point biserial, and distractors functionality. Conclusion: It has been observed that there is no difference in students' performance whether PBL or TBL is used for learning Basic Medical Science courses. Small group learning such as PBL needs more resources in comparison to large group learning as in TBL, therefore any institute can decide on the adopted learning strategy depending on its resources and the number of students.

Alvespimycin Exhibits Potential Anti-TGF-ß Signaling in the Setting of a Proteasome Activator in Rats with Bleomycin-Induced Pulmonary Fibrosis: A Promising Novel Approach.

Idiopathic pulmonary fibrosis (IPF) is an irreversible and life-threatening lung disease of unknown etiology presenting only a few treatment options. TGF-ß signaling orchestrates a cascade of events driving pulmonary fibrosis (PF). Notably, recent research has affirmed the augmentation of TGF-ß receptor (TßR) signaling via HSP90 activation. HSP90, a molecular chaperone, adeptly stabilizes and folds TßRs, thus intricately regulating TGF-ß1 signaling. Our investigation illuminated the impact of alvespimycin, an HSP90 inhibitor, on TGF-ß-mediated transcriptional responses by inducing destabilization of TßRs. This outcome stems from the explicit interaction of TßR subtypes I and II with HSP90, where they are clients of this cellular chaperone. It is worth noting that regulation of proteasome-dependent degradation of TßRs is a critical standpoint in the termination of TGF-ß signal transduction. Oleuropein, the principal bioactive compound found in Olea europaea, is acknowledged for its role as a proteasome activator. In this study, our aim was to explore the efficacy of a combined therapy involving oleuropein and alvespimycin for the treatment of PF. We employed a PF rat model that was induced by intratracheal bleomycin infusion. The application of this dual therapy yielded a noteworthy impediment to the undesired activation of TGF-ß/mothers against decapentaplegic homologs 2 and 3 (SMAD2/3) signaling. Consequently, this novel combination showcased improvements in both lung tissue structure and function while also effectively restraining key fibrosis markers such as PDGF-BB, TIMP-1, ACTA2, col1a1, and hydroxyproline. On a mechanistic level, our findings unveiled that the antifibrotic impact of this combination therapy likely stemmed from the enhanced degradation of both TßRI and TßRII. In conclusion, the utilization of proteasomal activators in conjunction with HSP90 inhibitors ushers in a promising frontier for the management of PF.

Ganetespib (STA-9090) augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma: Implications from preclinical data for a novel therapeutic approach.

Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its long-term effectiveness is limited by the emergence of resistance mechanisms. One such mechanism is the reduction of microvessel density and intratumoral hypoxia caused by prolonged sorafenib treatment. Our research has demonstrated that HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic conditions and N-Nitrosodiethylamine-exposed mice as well. This occurs through the inhibition of necroptosis on the one hand and the stabilization of HIF-1α on the other hand. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We found that ganetespib activated necroptosis and destabilized HIF-1α under hypoxia, thus enhancing the effectiveness of sorafenib. Additionally, we discovered that LAMP2 aids in the degradation of MLKL, which is the mediator of necroptosis, through the chaperone-mediated autophagy pathway. Interestingly, we observed a significant negative correlation between LAMP2 and MLKL. These effects resulted in a reduction in the number of surface nodules and liver index, indicating a regression in tumor production rates in mice with HCC. Furthermore, AFP levels decreased. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. These findings suggest that the combined therapy of ganetespib and sorafenib may offer a promising approach for the treatment of hepatocellular carcinoma by activating necroptosis, inhibiting macroautophagy, and exhibiting a potential antiangiogenic effect. Overall, continued research is critical to establish the full therapeutic potential of this combination therapy.

Androgen receptor blockade by flutamide down-regulates renal fibrosis, inflammation, and apoptosis pathways in male rats.

AIM: this study aims to explore the effect of androgen receptor (AR) blockade by flutamide on some renal pathologic changes such as inflammation, apoptosis, and fibrosis in male rats. MAIN METHODS: Firstly, we investigated the potential effect of AR blockade on renal inflammatory intermediates including IL-1ß, IL-6, TNF-α, NF-Òšß proteins, and the renal gene expression of NF-Қß. Besides inflammation, we also assessed the apoptosis pathways including the caspases 3 & 9, mTOR, pAKT proteins, and BAX gene expression. Besides inflammation and apoptosis pathways, we also investigated the effect of androgen blockade on renal fibrosis intermediates including vimentin, TGFß-1, α-SMA, MMP-9, collagen type-III, collagen type-IV, and the renal expression of the col1A1 gene. Besides previous pathological pathways, we assessed the expression of chloride channel protein-5 (ClC-5), as an important regulator of many renal pathological changes. Finally, we assessed the impact of previous pathological changes on renal function at biochemical and pathological levels. KEY FINDINGS: We found that AR blockade by flutamide was associated with the down-regulation of renal inflammation, apoptosis, and fibrosis markers. It was associated with expression down-regulation of IL-1ß & IL-6, TNF-α, NF-Қß, caspases 3 & 9, mTOR, MMP-9, collagens, TGFß-1, and α-SMA. Away from down-regulation, we also found that AR blockade has upregulated ClC-5 and pAKT proteins. SIGNIFICANCE: AR is a major player in androgens-induced nephrotoxicity. AR blockade downregulates renal fibrosis, inflammation, and apoptosis pathways. It may be helpful as a strategy for alleviation of renal side effects associated with some drugs. However; this needs further investigations.

Topiramate affords neuroprotection in diabetic neuropathy model via downregulating spinal GFAP/inflammatory burden and improving neurofilament production.

The current study aimed to test the neuroprotective action of topiramate in mouse peripheral diabetic neuropathy (DN) and explored some mechanisms underlying this action. Mice were assigned as vehicle group, DN group, DN + topiramate 10-mg/kg and DN + topiramate 30-mg/kg. Mice were tested for allodynia and hyperalgesia and then spinal cord and sciatic nerves specimens were examined microscopically and neurofilament heavy chain (NEFH) immunostaining was performed. Results indicated that DN mice had lower the hotplate latency time (0.46-fold of latency to licking) and lower von-Frey test pain threshold (0.6-fold of filament size) while treatment with topiramate increased these values significantly. Sciatic nerves from DN control mice showed axonal degeneration while spinal cords showed elevated GFAP (5.6-fold) and inflammatory cytokines (∼3- to 4-fold) but lower plasticity as indicated by GAP-43 (0.25-fold). Topiramate produced neuroprotection and suppressed spinal cord GFAP/inflammation but enhanced GAP-43. This study reinforces topiramate as neuroprotection and explained some mechanisms included in alleviating neuropathy.

Medical students' perception and academic performance after team-based and seminar-based learning in human anatomy.

Objectives: Student-centered educational strategies like problem-based learning (PBL), case-based learning (CBL), team-based learning (TBL), and seminars enhance group and self-learning. This study was carried out to evaluate students' achievements in anatomy topics delivered through TBL sessions and seminars and to survey student preferences regarding these two modalities in anatomy learning. Methods: TBL was conducted through individual readiness assurance tests (IRATs), group readiness assurance tests (GRATs), mini-lectures, and application exercises. Seminars included pretests, peer lecturing, and posttests. The performance of 117 students in three TBL sessions and three seminars was compared after standardizing the questions. The students were second-year (42), third-year (40), and fourth-year (35) students at the College of Medicine, University of Bisha, KSA, during the 2019/2020 academic year. Results: A gradual increase in the means of TBL grades was noticed among second-, third-, and four-year students (means ± SD: 68.6 ± 9.56, 82.8 ± 12.25, and 92.7 ± 4.70, respectively), but their seminar grades were nearly stationary (means ± SD: 80.0 ± 9.66, 85.11 ± 10.16, and 85.9 ± 8.80, respectively). Cohen's d-test to check the strength of the relationship between the two activities showed 1.03, 0.16, and 0.74 in the same order. We statistically analyzed perception and preference questionnaire results received from 39, 35, and 28 second-, third-, and four-year students, respectively. The majority of the students selected TBL as their preferred learning modality. However, their acceptance of the seminars was very poor. Conclusions: It can be concluded that TBL is more beneficial to the students, even in practical sciences like anatomy, most likely because group peer teaching enhances the sense of collegial competition, as opposed to the self-learning nature of seminars, which might suppress the sense of competition.

Saponin-rich extract of Tribulus terrestris alleviates systemic inflammation and insulin resistance in dietary obese female rats: Impact on adipokine/hormonal disturbances.

Tribulus terrestris saponins (TTS) have been longley used as an overall tonic and recent studies showed they influence inflammatory conditions. We examined the ameliorative effect of a commercial formula of a saponin-rich extract of TT in a model of dietary obesity in female rats focusing on their ability to control the inflammatory burden, insulin resistance (IR), adipokine expression and the related reproductive system pathologies. Female rats were fed with high fat diet (HFD) for 14 weeks to launch diet-induced obesity; they were assigned as: the obese control female rats (OFR) which received no treatment and TTS (5 and 10 mg/kg/day) treated rats; they were compared to a normal rat group. We determined the IR index, serum/tissue inflammatory cytokines, and adipose tissue adipokine expression and examined the secondary ovarian pathologies. Body weight gain, serum triglycerides and IR (>5-fold) in the OFR group were greater than the normal group; TTS lessened these parameters compared with the OFR group. TTS, at 10 mg/kg dose, ameliorated mRNA expression of leptin and visfatin genes in addition to serum inflammatory cytokine levels. Moreover, TTS corrected the hyperprolactinemia and other hormonal disturbances and ameliorated the ovarian pathologies. This study highlighted that the anti-inflammatory properties of TTS helped in alleviation of IR and body weight gain in OFR. Upon correction of obesity manifestations, the gonadal hormone dysregulations and ovarian pathologies were subsequently ameliorated. We can consider TTS as a promising candidate that may alleviate the inflammatory burden, IR and adipokine expression in obesity and hence prevent the secondary gonadal complications in female subjects if appropriate clinical studies are available.

Antitumor Activity of Nitazoxanide against Colon Cancers: Molecular Docking and Experimental Studies Based on Wnt/ß-Catenin Signaling Inhibition.

In colon cancer, wingless (Wnt)/ß-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/ß-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and ß-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/ß-catenin/glycogen synthase kinase-3ß (GSK-3ß) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/ß-catenin/GSK-3ß signaling.

Chemopreventive Effect of 5-Flurouracil Polymeric Hybrid PLGA-Lecithin Nanoparticles against Colon Dysplasia Model in Mice and Impact on p53 Apoptosis.

The use of 5-fluorouracil (5FU) is associated with multifaceted challenges and poor pharmacokinetics. Poly(lactic-co-glycolic acid)-lipid hybrid nanoparticles (PLNs)-based therapy has received attention as efficient carriers for a diversity of drugs. This study evaluated the in vivo chemotherapeutic and anti-proliferative efficacy of 5FU-loaded PLNs against 1,2-dimethylhydrazine (Di-MH) prompted colon dysplasia in mice compared to free 5FU. 5FU PLNs were prepared. Male Swiss albino mice were distributed to six experimental groups. Group 1: Saline group. All the other groups were injected weekly with Di-MH [20 mg/kg, s.c.]. Group 2: Di-MH induced colon dysplasia control group. Groups 3 and 4: Di-MH + free 5FU treated group [2.5 and 5 mg/kg]. Groups 5 and 6: Di-MH + 5FU-PLNs treated group [2.5 and 5 mg/kg]. Free 5FU and 5FU-PLNs doses were administered orally, twice weekly. Treatment with 5FU-PLNs induced a higher cytoprotective effect compared to free 5FU as indicated by lower mucosal histopathologic score and reduction in number of Ki-67 immunpositive proliferating nuclei. Additionally, there was significant upregulation of p53 and caspase 3 genes in colon specimens. Our results support the validity of utilizing the PLNs technique to improve the chemopreventive action of 5FU in treating colon cancer.

Retinoprotective effect of donepezil in diabetic mice involves mitigation of excitotoxicity and activation of PI3K/mTOR/BCl2 pathway.

Donepezil (DNPZ) has shown neuroprotective effect in many disorders. The current study tested the putative retinoprotection provided by donepezil in mouse diabetic retinopathy. Swiss albino mice were allocated to, 1] saline control, 2] diabetic, 3&4] diabetic+DNPZ (1 or 4 mg/kg). After induction of diabetes, mice were maintained for 8 weeks then DNPZ therapy was launched for 28 days. Retinas were isolated and used for histopathology and immunohistochemistry for caspase 3 and the anti-apoptotic protein, B-cell lymphoma 2 (BCl2). Retinas were examined for glutamate, acetylcholine and oxidation markers. Western blot analysis measured inflammatory cytokines, N-methyl-d-aspartate receptors (NMDARs), phosphorylated and total phosphatidylinositol-3 kinase and mTOR, BCl2 and cleaved caspase 3. Significant histopathological changes and decreased thickness were found in diabetic retinas (125.52 ± 2.85 vs. 157.15 ± 7.55 in the saline group). In addition, retinal glutamate (2.39-fold), inflammatory cytokines and NMDARs proteins (4.9-fold) were higher in the diabetic retinas. Western blot analysis revealed low ratio of phosphorylated/total PI3K (0.21 ± 0.043 vs. 1 ± 0.005) and mTOR (0.18 ± 0.04 vs. 1 ± 0.005), low BCl2 (0.28 ± 0.06 vs. 1 ± 0.005) and upregulated cleaved caspase 3 (5.18 ± 1.27 vs. 1 ± 0.05 in the saline group) versus the saline control. DNPZ ameliorated the histopathologic manifestations and to prevent the decrease in retinal thickness. DNPZ (4 mg/kg) improved phosphorylation of PI3K (0.76 ± 0.12 vs. 0.21 ± 0.04) and mTOR (0.59 ± 0.09 vs. 0.18 ± 0.04) and increased BCl2 (0.75 ± 0.08 vs. 0.28 ± 0.06) versus the diabetic control group. This study explained the retinoprotective effect of DNPZ in mouse diabetic retinopathy and highlighted that mitigation of excitotoxicity, improving phosphorylation of PI3K/mTOR and increasing BCl2 contribute to this effect.

The protective effect of biochanin A against rotenone-induced neurotoxicity in mice involves enhancing of PI3K/Akt/mTOR signaling and beclin-1 production.

Rotenone is an insecticide that generates oxidative stress in the CNS and induces locomotor dysfunction and neurodegeneration in rodents. Biochanin A [BioA] is an isoflavone with antioxidant and anti-inflammatory actions. The antioxidant and the modulatory action of BioA on PI3K/Akt/mTOR signaling and autophagy were tested in rotenone-Parkinsonian mice. Mice were allocated into; Group I: oil control group, Group II: rotenone group [1-mg/kg/48h, subcutaneously], group III: rotenone and BioA [10-mg/kg]. Rotenone injection resulted in locomotor disturbances in mice, degeneration in dopaminergic neurons [tyrosine hydroxylase-immunoreactive cells], low striatal dopamine, increased malondialdehyde and decreased level of glutathione. Neuroinflammation was evidenced by upregulation of astrocytes [glia fibrillary acidic protein, GFAP] and elevated levels of cytokines. The phosphorylation of PI3K/Akt/mTOR and the autophagy-related protein, beclin-1, were decreased significantly as indicated by Western blot analysis. BioA treatment enhanced locomotor activity and afforded nigral neuroprotection. The mechanism by which BioA produced this effect includes increased antioxidant defenses, lessened proinflammatory cytokines, increased phosphorylation of PI3K/Akt/mTOR proteins and upregulated beclin-1. Importantly, BioA suppressed the striatal astrocyte marker [GFAP]. Overall, the currents study highlighted that BioA activates PI3K/Akt/mTOR signaling and enhances beclin-1 leading to neuroprotection for nigral dopaminergic neurons.

Efflux MexAB-Mediated Resistance in P. aeruginosa Isolated from Patients with Healthcare Associated Infections.

Today, one of the most important challenges for physicians is the adequate treatment of infections due to multidrug resistant organism (MDR). Pseudomonas aeruginosa is considered an opportunistic organism causing different types of healthcare associated infections (HAIs). We aimed to investigate the MDR and pandrug resistance (PDR) rate in P. aeruginosa in our region and detect efflux-pump mexAB genes and the proposed binding interactions of five different categories of antimicrobial agents with the mexB pump. A total of 180 non-duplicated P. aeruginosa strains were isolated from patients with HAIs in the Suez Canal University Hospital. Phenotypically, minimum inhibitory concentration (MIC) was done for all MDR and PDR strains before and after addition of efflux pump inhibitor carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Molecular detection of mexA and mexB genes was done by using polymerase chain reaction (PCR). Most of the isolated strains (126 strains) were MDR (70%); only 10 samples (5.5%) were PDR. MexA and mexB genes were detected in 88.2% (120 strains) and 70.5% (96 strains) of stains, respectively. All PDR strains (10 stains) carried both mexA and mexB genes. Efflux mexAB genes were detected in all MDR and PDR strains (136 strains). Molecular modeling studies were performed to investigate the modes of intermolecular binding interactions between the antimicrobial agents and mexB key amino acids that resulted in MDR and PDR. The current study reported high prevalence of MDR and PDR P. aeruginosa in patients with HAIs in the Suez Canal University Hospitals.